G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons

Masoud Ghamari-Langroudi; Gregory J Digby; Julien A Sebag; Glenn L Millhauser; Rafael Palomino; Robert Matthews; Taneisha Gillyard; Brandon L Panaro; Iain R Tough; Helen M Cox; Jerod S Denton; Roger D Cone

doi:10.1038/nature14051

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G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons

Journal article

Peer reviewed

G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons

Masoud Ghamari-Langroudi, Gregory J Digby, Julien A Sebag, Glenn L Millhauser, Rafael Palomino, Robert Matthews, Taneisha Gillyard, Brandon L Panaro, Iain R Tough, Helen M Cox, …

Nature (London), Vol.520(7545), pp.94-98

04/02/2015

DOI: 10.1038/nature14051

PMCID: PMC4383680

PMID: 25600267

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Abstract

The regulated release of anorexigenic α-melanocyte stimulating hormone (α-MSH) and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the central nervous system has a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 receptor (MC4R); existing data show that α-MSH is an agonist that couples the receptor to the Gαs signalling pathway, while AgRP binds competitively to block α-MSH binding and blocks the constitutive activity mediated by the ligand-mimetic amino-terminal domain of the receptor. Here we show that, in mice, regulation of firing activity of neurons from the paraventricular nucleus of the hypothalamus (PVN) by α-MSH and AgRP can be mediated independently of Gαs signalling by ligand-induced coupling of MC4R to closure of inwardly rectifying potassium channel, Kir7.1. Furthermore, AgRP is a biased agonist that hyperpolarizes neurons by binding to MC4R and opening Kir7.1, independently of its inhibition of α-MSH binding. Consequently, Kir7.1 signalling appears to be central to melanocortin-mediated regulation of energy homeostasis within the PVN. Coupling of MC4R to Kir7.1 may explain unusual aspects of the control of energy homeostasis by melanocortin signalling, including the gene dosage effect of MC4R and the sustained effects of AgRP on food intake.

GTP-Binding Protein alpha Subunits, Gs

Melanocortins - metabolism

Humans

Male

Receptor, Melanocortin, Type 4 - metabolism

Receptor, Melanocortin, Type 4 - genetics

Signal Transduction - genetics

Agouti-Related Protein - metabolism

Eating - genetics

alpha-MSH - metabolism

Action Potentials

Paraventricular Hypothalamic Nucleus - cytology

Animals

Energy Metabolism

HEK293 Cells

Female

Ligands

Mice

Neurons - metabolism

Potassium Channels, Inwardly Rectifying - metabolism

Homeostasis - genetics

Details

Title: Subtitle: G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons
Creators: Masoud Ghamari-Langroudi - Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
Gregory J Digby - Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
Julien A Sebag - Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
Glenn L Millhauser - Department of Chemistry &Biochemistry, University of California, Santa Cruz, California 95064, USA
Rafael Palomino - Department of Chemistry &Biochemistry, University of California, Santa Cruz, California 95064, USA
Robert Matthews - Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
Taneisha Gillyard - 1] Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA Department of Pharmacology, Meharry Medical College, Nashville, Tennessee 37208, USA
Brandon L Panaro - Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
Iain R Tough - King's College London, Wolfson Centre for Age-Related Diseases, Guy's Campus, London SE1 1UL, UK
Helen M Cox - King's College London, Wolfson Centre for Age-Related Diseases, Guy's Campus, London SE1 1UL, UK
Jerod S Denton - 1] Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
Roger D Cone - Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA
Resource Type: Journal article
Publication Details: Nature (London), Vol.520(7545), pp.94-98
DOI: 10.1038/nature14051
PMID: 25600267
PMCID: PMC4383680
NLM abbreviation: Nature
ISSN: 0028-0836
eISSN: 1476-4687
Publisher: England
Grant note: R25 GM059994 / NIGMS NIH HHS DK020593 / NIDDK NIH HHS R01 DK082884 / NIDDK NIH HHS R01 DK070332 / NIDDK NIH HHS R01 DK064265 / NIDDK NIH HHS P30 DK020593 / NIDDK NIH HHS F31 DK102343 / NIDDK NIH HHS P60 DK020593 / NIDDK NIH HHS G12 MD007586 / NIMHD NIH HHS R01DK064265 / NIDDK NIH HHS R01DK070332 / NIDDK NIH HHS 5R01 DK082884-03 / NIDDK NIH HHS
Language: English
Date published: 04/02/2015
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984025674402771

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